This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process to prepare (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride salt of formula I: 
Among the problems in cancer chemotherapy is the development of resistance to treatment regimens. Tumors that respond well to a particular drug or drugs initially often develop a tolerance to the drug(s).
This disease state, called multi-drug resistance, is discussed in greater detail in Kuzmich and Tew, xe2x80x9cDetoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,xe2x80x9d particularly section VII xe2x80x9cThe Multidrug-Resistant Phenotype (MDR),xe2x80x9d Medical Research Reviews, Vol. 11, No. 2, 185-217, particularly 208-213 (1991); and in Georges, Sharom and Ling, xe2x80x9cMultidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,xe2x80x9d Advances in Pharmacology, Vol. 21, 185-220 (1990).
U.S. Pat. Nos. 5,643,909 and 5,654,304, incorporated herein by reference, disclose a series of 10,11-methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride disclosed therein, is currently under development as a pharmaceutical agent. The present invention involves an improved process to prepare (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (compound of formula I), wherein the chemistry is more efficient and adaptable to large scale processing in anticipation of development needs.
The art disclosed in U.S. Pat. No. 5,776,939, and U.S. Pat. No. 5,643,909 both incorporated herein by reference, and PCT Patent Applications (Publication numbers WO 94/24107 and 98/22112) teach the use of 1-formylpiperazine to introduce the piperazine group of the compound of formula II 
Compound II is a mixture of syn isomer (III) 
and anti isomer (IV) 
The process as disclosed in U.S. Pat. Nos. 5,643,909 and 5,654,304 (represented by scheme A, below) involves (a) chromatographic separation(s) of the formyl piperazine compound; and (b) deformylation of the formyl piperazine compound to provide compound IV. 
The process of the present invention uses piperazine to react with the (1axcex1,6xcex1,10bxcex1)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene compound or derivative, instead of formylpiperazine.
The process of the present invention is advantageous because piperazine is readily available in commercial quantities whereas 1-formylpiperazine, which was utilized in the process disclosed in U.S. Pat. No. 5,643,909 is often not readily available in commercial quantities. Additionally piperazine enjoys a significant cost advantage over 1-formylpiperazine.
The use of piperazine instead of 1-formylpiperazine is a significant advancement over the prior art because it obviates the need to deformylate or hydrolyze off the formyl group (step 6, scheme A), thereby providing fewer operational steps. U.S. Pat. No. 5,643,909 teaches the separation of the 1-formylpiperazine compounds by chromatography or repeated crystallizations. The present invention obviates the need for chromatographic separations of the formylpiperazine diastereomeric addition compounds (see step 4, scheme A).
The present invention provides a process for preparing a compound of the formula (IVa): 
wherein HX is an acid, comprising the steps of:
(a) dissolving a compound of formula (II) 
in acetonitrile to form a solution;
(b) crystallizing a syn stereoisomer compound of formula (III) 
from the solution of (II);
(c) removing the acetonitrile from the filtrate to provide a mixture enriched in an anti stereoisomer compound of formula (IV) 
(d) adding an acid, and a solvent selected from the group consisting of methylene chloride, ethanol and ethyl acetate to said enriched mixture; and
(e) crystallizing the anti-stereoisomer compound of formula (IVa).
The present invention also provides a process for preparing a compound of formula (IVa), 
comprising the steps of:
(a) converting 10,11-dibenzosuberenone (i), 
to the alcohol (ii), 
(b) reacting alcohol (ii) in one operational step with a halogenating agent to form (1axcex1,6xcex1,10bxcex1)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]-cyclopropa[c]cycloheptene (iii); 
where X is I, Br, or Cl;
(c) reacting (1axcex1,6xcex1,10bxcex1)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene (iii) with piperazine in a solvent to form the mixture of syn (III) 
and anti (IV) 
piperazine compounds, and
(d) separating the compound of formula III from the compound of formula IV by the method of the invention.
The present invention also provides a process for preparing a compound of formula (I) from the anti stereoisomer IVa, according to the invention, comprising the steps of:
(a) reacting the anti-stereoisomer (IVa) as the free base, with (R)-1-(5-quinolinyloxy)-2,3-epoxypropane to provide compound of formula (V); 
and
(b) optionally reacting hydrogen chloride with compound (V) to form a compound of formula (I): 
The present invention further provides a process for preparing the syn isomer compound (III) and pharmaceutically acceptable salts thereof, by the method of the invention.
The terms and abbreviations used herein have their normal meanings unless otherwise designated. For example xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cNxe2x80x9d refers to normal or normality; xe2x80x9cmmolxe2x80x9d refers to millimole or millimoles; xe2x80x9cgxe2x80x9d refers to gram or grams; xe2x80x9cdxe2x80x9d refers to density, xe2x80x9cmin.xe2x80x9d refers to minutes, xe2x80x9cmLxe2x80x9d means milliliter or milliliters; xe2x80x9cMxe2x80x9d refers to molar or molarity; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cmmxe2x80x9d refers to millimeters; xe2x80x9ccmxe2x80x9d refers to centimeters; xe2x80x9cnmxe2x80x9d refers to nanometers; and xe2x80x9crtxe2x80x9d refers to retention time. The term xe2x80x9chaloxe2x80x9d refers to fluoro, bromo, chloro and iodo.
As used herein the term xe2x80x9chalogenating agentxe2x80x9d refers to halogenic acids or other acidic groups capable of converting alcohols to halides. Illustrative halogenating agents include hydrogen bromide, hydrogen chloride, hydrogen iodide, thionyl chloride, oxalyl chloride, phosphorus trichloride or pentachloride, and the like.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to all non-toxic organic or inorganic acid addition salts. Illustrative inorganic acids or xe2x80x9cacidic groupsxe2x80x9d which form salts include hydrochloric, hydrobromic, sulfuric, phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative acids or xe2x80x9cacidic groupsxe2x80x9d which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and 2-hydroxyethane sulfonic acid. Preferred acids include those selected from the group comprising of hydrobromic acid, hydrochloric acid, camphorsulfonic acid, p-toluenesulfonic acid, and sulfuric acid. A particularly preferred acidic group is hydrochloric acid. Acid addition salts formed from these acids can exist in either hydrated or substantially anhydrous form, all of which are within the scope of this invention.
The terms xe2x80x9cHX,xe2x80x9d xe2x80x9cacidic group,xe2x80x9d and xe2x80x9cacidxe2x80x9d are synonymous as used herein.
The compounds of formula II may be prepared according to the following steps illustrated in Scheme B, starting from 5H-dibenzo[a,d]cyclohepten-5-one (dibenzosuberenone), which is commercially available, e.g., from Aldrich Chemical Company, Milwaukee, Wis. Other reactants are likewise commercially available or may be readily prepared by those skilled in the art. A particularly preferred embodiment of this invention provides a procedure that combines steps 1 and 2 (see Scheme B below) in one operational step. 
Step 1: A solution of an alkali halodifluoroacetate such as sodium chlorodifluoroacetate in a solvent (for example, glyme, diglyme) is added over a period of 4 to 8 hours (preferably 6 hours) to a solution of dibenzosuberenone (for example in diglyme) with stirring and under nitrogen, maintaining the reaction temperature at 160xc2x0-165xc2x0 C. Other reaction temperatures may be employed depending upon the reactants used, as described in Ciganek et al., xe2x80x9cImine Analogues of Tricyclic Antidepressants,xe2x80x9d J. Med. Chem., 1981, 24,336-41; or in Coyne and Cusic, xe2x80x9cAminoalkyldibenzo[a,e]cyclopropa[c]cycloheptene Derivatives. A Series of Potent Antidepressants,xe2x80x9d J. Med. Chem., 1974, Vol. 17, No. 1, 72-75. The reaction mixture is brought to room temperature, then poured into water and extracted (e.g., with diethylether or pentane). The 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one is isolated and purified by conventional means, for example, the organic phase is washed with water, dried (e.g., over Na2SO4), evaporated, and the residue is recrystallized (e.g., from ethanol, and optionally recrystallized again, e.g., from acetone/hexane).
Step 2: A solution of the 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one in a solvent (e.g., THF/methanol) is cooled typically to between 0xc2x0 C. and 25xc2x0 C., and a reducing agent (e.g., lithium borohydride or sodium borohydride) is added in portions. The reaction mixture is allowed to come to room temperature and stirred for 1 to 5 hours preferably 2 hours, then poured into water. The product is isolated (e.g., by filtration) and purified by conventional means (e.g., washed with water and dried) to give the corresponding (1axcex1,6xcex2,10bxcex1)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol (ii).
Preferably steps 1 and 2 may be accomplished in one processing step by heating a solution of dibenzosuberenone in triethylene glycol dimethyl ether to between 180xc2x0 C. and 210xc2x0 C., followed by slow addition of a solution of chlorodifluoroacetic acid, lithium salt in ethylene glycol dimethyl ether. The ethylene glycol dimethyl ether is distilled from the reaction as the salt addition proceeded. Gas chromatographic analysis of an aliquot is utilized to indicate complete or near complete consumption of the 5H-dibenzo[a,d]cyclohepten-5-one. The reaction is cooled to ambient temperature and then combined with a mixture of ethyl acetate and diatomaceous earth. The solids are removed by filtration and washed with ethyl acetate. The washes and filtrate are combined and the ethyl acetate is removed by concentration under vacuum. The concentrate is cooled, followed by addition of sodium borohydride solution sufficient to effect complete or near complete reduction. After stirring for 1-5 h, preferably 2-4 hours, the reaction is quenched by careful addition of a methanolic HCl solution. The suspension is stirred for 30 minutes and the crude product is collected by filtration, washed with 1:1 methanol-water and dried to a dark brown solid. The crude product is slurried in methylene chloride, filtered and dried to afford (1axcex1,6xcex2,10bxcex1)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo-[a,e]cyclopropa[c]cyclohepten-6-ol (ii).
Step 3: A solution of the (1axcex1,6xcex2,10bxcex1)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol in a suitable solvent (e.g., dichloromethane) is cooled (e.g., in an ice bath) followed by addition of a halogenating agent. Preferred halogenating agents are hydrogen bromide, hydrogen chloride, hydrogen iodide, thionyl chloride, oxalyl chloride, phosphorus trichloride or pentachloride, and the like. Most preferred are hydrogen chloride and hydrogen bromide. The reaction is maintained at a temperature of between 40xc2x0 to 70xc2x0 C., preferably 50xc2x0 C., for 2 to 5 hours (preferably 4 hours). The reaction mixture is evaporated to dryness, affording a mixture of (1axcex1,6xcex1,10bxcex1)-6-halo-1,1-difluoro-1,1,a,6,10b-tetrahydrodibenzo[a,e]-cyclopropa[c]cycloheptene and the corresponding syn isomer (1axcex1,6xcex2,10bxcex1)-6-halo-1,1-difluoro-1,1,a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene. In the case of the bromo derivative the bromination reaction provides the anti-stereoisomer ((1axcex1,6xcex1,10bxcex1)-6-bromo-1,1-difluoro-1,1,a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene) (iii) exclusively. Preparation of the (1axcex1,6xcex1,10bxcex1)-6-bromo-1,1-difluoro-1,1,a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene derivative (iii) is preferably accomplished by reacting the (1axcex1,6xcex2,10bxcex1)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol (ii) with hydrogen bromide.
Combined steps 4 and 5: The (1axcex1,6xcex1,10bxcex1)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene product of step 3, is with or without further purification, dissolved in acetonitrile. Piperazine is introduced by nucleophilic displacement of the halide e.g., by adding piperazine with stirring, preferably under dry nitrogen. The reaction temperature is maintained between 50xc2x0 C. to 100xc2x0 C., preferably between 70xc2x0 C. to 90xc2x0 C., for 1 to 6 hours, preferably 2 hours. The mixture of syn and anti-stereoisomers (II) is preferably separated by crystallization of the syn stereoisomer from the acetonitrile reaction mixture. This is followed by removal of the remaining acetonitrile and replacement with hydrogen bromide or other suitable acid and a solvent selected from methylene chloride, ethanol and ethyl acetate. The purified (1axcex1,6xcex1,10bxcex1)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)-piperazine, acid salt compound (IVa) is afforded after crystallization.
The isolated syn isomer product III from above may be dried, used directly or optionally further purified by methods known in the arts, e.g., crystallization, chromatography. The syn isomer compound of formula (III) may optionally be acidified to form a pharmaceutically acceptable acid salt.
The acid salt compound (Iva) may be converted to the compounds of formula I as illustrated in scheme C below: 
(1axcex1,6xcex1,10bxcex1)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)piperazine, acid salt compound (IVa) after conversion to the free base (IV) by neutralization, is reacted with a solution of the epoxide, (R)-1-(5-quinolinyloxy)2,3-epoxypropane (compound of formula 8), in a solvent such as ethanol or isopropanol, to produce (2R)-anti-5-{3-[4-(10,11-difluoromethano-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline (V). Acid salts of (V) may be prepared by methods known to those skilled in the art. The preferred trihydrochloride salt, anti-5-{3-[4-(10,11-difluoromethano-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (I), may be prepared by addition of hydrogen chloride in diethyl ether (e.g., 3 molar equivalents to form the trihydrochloride (salt) at 0-15xc2x0 C. followed by, for example, recrystallization from ethanol.
The syn isomer compound of formula (III) isolated as described supra, can be acidified to form the acid salt compound of formula (IIIa): 
Optionally, the syn isomer compound of formula (III) can be utilized to produce the corresponding syn-5-{3-[4-(10,11-difluoromethano-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride compound of formula (XII) 
essentially as shown above for the free base of the anti isomer (IVa).